WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA

Aging (Albany NY). 2021 Mar 26;13(8):11135-11149. doi: 10.18632/aging.202770. Epub 2021 Mar 26.


Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.

Keywords: I/R injury; Wilms' tumor 1-associating protein; endoplasmic reticulum stress; m6A modification; myocardial infarction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics*
  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Butylamines / pharmacology
  • Butylamines / therapeutic use
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / genetics
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Methylation
  • Myocardial Infarction / complications*
  • Myocardial Infarction / genetics
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / genetics*
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • RNA Splicing Factors / antagonists & inhibitors
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / metabolism*
  • RNA, Messenger / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • 4-phenylbutylamine
  • ATF4 protein, human
  • Butylamines
  • Cell Cycle Proteins
  • RNA Splicing Factors
  • RNA, Messenger
  • WTAP protein, human
  • Activating Transcription Factor 4
  • N-methyladenosine
  • Adenosine